Affinage

GTF3C2

General transcription factor 3C polypeptide 2 · UniProt Q8WUA4

Round 2 corrected
Length
911 aa
Mass
100.7 kDa
Annotated
2026-04-28
50 papers in source corpus 17 papers cited in narrative 17 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GTF3C2 (TFIIIC110) is a core subunit of the human TFIIIC2 complex that recognizes B-box promoter elements and is essential for RNA polymerase III transcription of tRNA, 5S rRNA, and other non-coding RNA genes. GTF3C2 enters the nucleus, assembles with other TFIIIC subunits, and is recruited to Pol III gene loci, yet its overexpression alone is insufficient to activate Pol III transcription, indicating that TFIIIC2 complex integrity and additional regulatory inputs are required (PMID:16822860); these inputs include physical association of the TFIIIC complex with mTOR, which couples nutrient sensing to Pol III output (PMID:20543138), interaction with NF1 to support accurate termination and reinitiation (PMID:11118217), and transcriptional control of GTF3C2 itself by Sp1 (activated upstream by GATA4 and TFAP2A) (PMID:32115405, PMID:35038452). GTF3C2 is subject to proteolytic degradation by μ-calpain downstream of Leishmania gp63/PAR1/Ca²⁺ signaling in macrophages, which suppresses B-box-dependent ncRNA transcription and promotes pathogen survival (PMID:21149457). Beyond canonical Pol III targets, GTF3C2 drives hepatocellular carcinoma proliferation by transcriptionally activating USP21 to stabilize MEK2 and engage ERK1/2 signaling, and it accumulates in the nucleus of cytokine-stimulated endothelial cells where it regulates claudin tight junction gene transcription (PMID:40385937, PMID:38806818).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1994 Medium

    Identification of GTF3C2 as a novel human gene provided the molecular entry point for studying its function in transcription.

    Evidence cDNA cloning from KG-1 myeloid cell line with full-length sequencing

    PMID:7584026

    Open questions at the time
    • No function assigned at this stage
    • Relationship to Pol III machinery not yet established
  2. 2000 High

    Demonstration that NF1 physically interacts with TFIIIC110 and TFIIIC220 and that this interaction supports accurate termination and reinitiation of Pol III transcription established GTF3C2 as a functional hub within the TFIIIC2 complex.

    Evidence Protein purification, co-immunoprecipitation, immunodepletion, and in vitro transcription on VA1 template with mutational analysis

    PMID:11118217

    Open questions at the time
    • Structural basis of NF1–TFIIIC110 interaction undefined
    • In vivo relevance of NF1–TFIIIC interaction at endogenous Pol III loci not tested
  3. 2006 High

    Showing that induced GTF3C2 enters the nucleus, binds other TFIIIC subunits, and occupies tRNA and 5S rRNA loci — yet fails to increase Pol III transcript levels — demonstrated that TFIIIC110 abundance alone is not rate-limiting for Pol III transcription.

    Evidence Doxycycline-inducible expression, ChIP at endogenous Pol III gene loci, RT-PCR in HeLa and HEK293 cells

    PMID:16822860

    Open questions at the time
    • Identity of the rate-limiting cofactors required alongside GTF3C2 not established
    • Post-translational regulation of endogenous GTF3C2 not addressed
  4. 2010 High

    Discovery that mTOR associates with TFIIIC through a TOR signaling motif and is recruited to Pol III gene loci linked nutrient/growth-factor sensing directly to the TFIIIC complex containing GTF3C2.

    Evidence Co-immunoprecipitation, ChIP, proximity ligation assay, in vitro kinase assay

    PMID:20543138

    Open questions at the time
    • Whether mTOR directly phosphorylates GTF3C2 or other TFIIIC subunits at specific sites not resolved
    • Functional consequence of mTOR–TFIIIC interaction on individual Pol III target gene output not quantified
  5. 2010 High

    Leishmania gp63 activates a PAR1/Ca²⁺/μ-calpain cascade that proteolytically degrades GTF3C2, suppressing B-box ncRNA transcription — the first demonstration that pathogen-induced GTF3C2 destruction modulates Pol III output in innate immune cells.

    Evidence Western blot, Ca²⁺ measurements, protease inhibitor experiments, avirulent gp63-negative parasite controls in macrophages; extended to M2-polarized macrophages with LPG/gp63 mutant parasites

    PMID:21149457 PMID:21165676

    Open questions at the time
    • Specific calpain cleavage site(s) on GTF3C2 not mapped
    • Whether GTF3C2 degradation is necessary and sufficient for Leishmania intracellular survival not formally tested
  6. 2020 High

    Identification of Sp1 as a direct transcriptional activator of GTF3C2 via the GTF3C2P2 promoter established a transcription-factor cascade controlling Pol III output through GTF3C2 expression levels.

    Evidence ChIP, reporter assay, shRNA knockdown and overexpression in HeLa, 293T, and SaOS2 cells

    PMID:32115405

    Open questions at the time
    • Relative contributions of alternative GTF3C2 promoters to total expression unknown
    • Signal transduction events upstream of Sp1 that regulate GTF3C2 not fully mapped
  7. 2022 High

    Placing GATA4 upstream of Sp1 and subsequently GTF3C2 extended the regulatory hierarchy controlling Pol III transcription and linked oncogenic GATA4 activity to GTF3C2 expression and tumor cell proliferation.

    Evidence ChIP at endogenous loci, reporter assays, shRNA epistasis, cell proliferation assays in SaOS2 cells

    PMID:35038452

    Open questions at the time
    • Whether GATA4–Sp1–GTF3C2 axis operates in non-transformed tissues not tested
    • Direct comparison of GATA4 versus TFAP2A contribution to GTF3C2 levels not performed
  8. 2024 Medium

    Nuclear accumulation of GTF3C2 in cytokine-stimulated endothelial cells and its regulation of claudin-8 and claudin-4 transcription revealed a non-canonical role for GTF3C2 in tight junction gene control and barrier function.

    Evidence Nuclear fractionation, transcription factor binding analysis, Transwell barrier assay in porcine PMVECs treated with IL-1β and TNF-α

    PMID:38806818

    Open questions at the time
    • Whether GTF3C2 binds claudin promoters directly or acts through Pol III-independent intermediates not resolved
    • Mechanism of cytokine-induced nuclear accumulation of GTF3C2 unknown
    • Replication in human endothelial cells needed
  9. 2025 High

    GTF3C2 transcriptionally activates USP21, which stabilizes MEK2 and activates ERK1/2 signaling to drive hepatocellular carcinoma proliferation — the first defined oncogenic mechanism for GTF3C2 beyond general Pol III transcription enhancement.

    Evidence Luciferase reporter, shRNA/overexpression epistasis rescue, EdU/colony formation assays, subcutaneous xenograft in mice

    PMID:40385937

    Open questions at the time
    • Whether GTF3C2 activates USP21 through canonical Pol III or Pol II promoter elements not established
    • Mutational mapping of GTF3C2 domains required for USP21 activation absent
    • Relevance to other cancer types not explored

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the structural basis of GTF3C2 within the TFIIIC2 holocomplex, the identity of its direct DNA-binding domains versus those contributed by other TFIIIC subunits, the complete catalog of post-translational modifications that regulate its activity, and whether its non-canonical gene-regulatory roles (claudin genes, USP21) proceed through Pol III or Pol II mechanisms.
  • No high-resolution structure of human TFIIIC2 with GTF3C2 resolved
  • Genome-wide occupancy of GTF3C2 independent of other TFIIIC subunits not mapped
  • Functional significance of EGF-induced phosphorylation sites on GTF3C2 not determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0140223 general transcription initiation factor activity 3
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 1
Partners
GTF3C1MTORNF1SP1USP21
Complex memberships
TFIIIC2

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 GTF3C2 (KIAA0004) was first identified as a novel human gene by cDNA cloning from human immature myeloid cell line KG-1, with its coding sequence predicted from analysis of randomly sampled cDNA clones. cDNA library screening, sequence analysis DNA research Medium 7584026
2000 TFIIIC110 (GTF3C2), a subunit of human TFIIIC2, physically interacts with NF1 protein family members; NF1 binds specifically to two subunits of TFIIIC2 (TFIIIC220 and TFIIIC110/GTF3C2) and this interaction facilitates accurate termination and multiple-round reinitiation of transcription by RNA polymerase III on the VA1 gene template. Protein purification, peptide sequence analysis, co-immunoprecipitation, immunodepletion, in vitro transcription assay, mutational analysis The EMBO journal High 11118217
2004 TFIIIC110 (GTF3C2) levels are not increased upon MVM parvovirus infection or NS1 expression in mouse fibroblasts, even though SINE (B1 and B2) transcripts are elevated, indicating that upregulation of SINE expression is not driven by increased GTF3C2/TFIIIC110 levels. Differential display, primer extension, Western blot, transient transfection Virology Medium 15351211
2005 Multiple alternative promoters for the GTF3C2 gene were identified in genome-wide analysis of human transcriptional start sites, indicating that GTF3C2 expression is subject to complex transcriptional regulation through multiple promoter usage. 5'-end sequencing of full-length cDNAs from 164 oligo-cap libraries, bioinformatic clustering of transcriptional start sites Genome research Medium 16344560
2006 GTF3C2 (TFIIIC110) was detected as a phosphoprotein in EGF-stimulated HeLa cells with specific phosphorylation sites identified by mass spectrometry, indicating that GTF3C2 undergoes dynamic phosphorylation in response to growth factor signaling. Large-scale phosphoproteomics by LC-MS/MS in EGF-stimulated HeLa cells Cell Medium 17081983
2006 Induced expression of TFIIIC110 (GTF3C2) in HeLa and HEK293 cells showed that the protein enters the nucleus, binds other TFIIIC subunits, and is recruited to tRNA and 5S rRNA gene loci in vivo, but overexpression alone has little to no effect on RNA polymerase III transcript levels, arguing against a simple model in which TFIIIC110 induction is sufficient to activate Pol III transcription. Transient transfection, stable doxycycline-inducible cell lines, chromatin immunoprecipitation (ChIP), RT-PCR Nucleic acids research High 16822860
2010 mTOR kinase associates with TFIIIC (the complex containing GTF3C2/TFIIIC110) and is recruited to tRNA and 5S rRNA gene loci through a TOR signaling motif in TFIIIC; this interaction connects the mTOR nutrient-sensing pathway directly to RNA polymerase III-dependent transcription. Co-immunoprecipitation, ChIP, proximity ligation assay, in vitro kinase assay Proceedings of the National Academy of Sciences of the United States of America High 20543138
2010 In Leishmania-infected macrophages, the surface protease gp63 of Leishmania activates the thrombin receptor PAR1, raising cytosolic Ca2+ and thereby activating μ-calpain, which proteolytically degrades TFIIIC110 (GTF3C2) to inhibit expression of B-box-containing non-coding RNA genes transcribed by RNA polymerase III. Western blot, protease inhibitor experiments, Ca2+ measurements, RNA analysis, avirulent strain controls The Journal of biological chemistry High 21149457
2010 In alternatively activated M2 macrophages, Leishmania requires both surface gp63 and LPG to down-regulate TFIIIC110 (GTF3C2), thereby repressing B-box-containing Pol III-transcribed ncRNA gene promoters; this effect is selective for M2 macrophages and correlates with permissiveness to Leishmania infection. Western blot, RNA analysis, pharmacological and genetic dissection with defined Leishmania surface mutants Molecular and cellular biochemistry Medium 21165676
2015 GTF3C2 was identified as a protein interaction partner in large-scale affinity-purification mass spectrometry (BioPlex) of HEK293T cells, placing it within protein communities consistent with its role in the RNA Pol III transcription machinery. High-throughput AP-MS (BioPlex), 2,594 bait proteins Cell Low 26186194
2017 GTF3C2 was identified within protein communities in BioPlex 2.0, the largest AP-MS human interactome, consistent with its membership in the TFIIIC complex. High-throughput AP-MS (BioPlex 2.0), >25% of protein-coding genes as baits Nature Low 28514442
2020 Sp1 transcription factor directly controls GTF3C2 expression by binding to Sp1 sites in the GTF3C2 promoter 2 (GTF3C2P2) and promoting occupancy of TBP, TFIIAα, and p300 at this promoter; Sp1 knockdown reduces GTF3C2 expression and Pol III-directed transcription, while Sp1 overexpression enhances them, linking Sp1 to Pol III transcription via GTF3C2. Reporter gene assay, ChIP, shRNA knockdown, overexpression, RT-PCR, Western blot in HeLa, 293T, and SaOS2 cells The Journal of biological chemistry High 32115405
2021 GTF3C2 was identified in the BioPlex 3.0 proteome-scale interaction network and its interactions were found to differ between 293T and HCT116 cell lines, suggesting cell-type-specific regulation of TFIIIC complex assembly. AP-MS (BioPlex 3.0), two-cell-line comparison Cell Low 33961781
2022 GATA4 promotes RNA polymerase III-directed transcription and tumor cell proliferation by activating Sp1 gene transcription (via GATA4 binding to the Sp1 promoter), which in turn activates BRF1 and GTF3C2 expression; GATA4 depletion reduces GTF3C2 expression and decreases Pol III machinery occupancy at Pol III target gene loci. ChIP, RT-PCR, Western blot, promoter reporter assays, shRNA knockdown, cell proliferation assays in SaOS2 cells The Journal of biological chemistry High 35038452
2023 TFAP2A (AP-2α) transcription factor activates GTF3C2 expression as part of a program promoting Pol III-directed transcription; TFAP2A was found to positively modulate assembly of the Pol III transcription machinery at Pol III target genes, with GTF3C2 being one of the Pol III transcription-related factors whose expression is induced by TFAP2A. ChIP, RT-PCR, Western blot, shRNA knockdown, cell proliferation assays The Journal of biological chemistry Medium 36707053
2024 GTF3C2 accumulates in the nucleus of pulmonary microvascular endothelial cells (PMVECs) treated with IL-1β and TNF-α (cytokines released by HP-PRRSV-infected macrophages) and regulates transcription of claudin-8 and claudin-4 tight junction proteins, thereby contributing to endothelial barrier disruption in acute lung injury. Nuclear fractionation, transcription factor binding analysis, cytokine treatment, Transwell barrier assay, gene expression analysis in porcine PMVECs Cellular and molecular life sciences Medium 38806818
2025 GTF3C2 promotes hepatocellular carcinoma cell proliferation by transcriptionally activating USP21 (ubiquitin-specific peptidase 21), which subsequently stabilizes MEK2 protein and activates the ERK1/2 signaling pathway; GTF3C2 knockdown suppressed proliferation in vitro and tumor growth in vivo, while co-overexpression of USP21 and MEK2 rescued proliferation inhibited by GTF3C2 knockdown. Luciferase reporter assay, RT-qPCR, Western blot, CCK-8/EdU/colony formation assays, shRNA knockdown, overexpression, subcutaneous xenograft mouse model Journal of clinical and translational hepatology High 40385937

Source papers

Stage 0 corpus · 50 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2006 A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nature biotechnology 1336 16964243
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2014 Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes. Journal of proteomics 215 25281560
2016 An organelle-specific protein landscape identifies novel diseases and molecular mechanisms. Nature communications 211 27173435
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
1994 Prediction of the coding sequences of unidentified human genes. I. The coding sequences of 40 new genes (KIAA0001-KIAA0040) deduced by analysis of randomly sampled cDNA clones from human immature myeloid cell line KG-1. DNA research : an international journal for rapid publication of reports on genes and genomes 207 7584026
2013 PRP19 transforms into a sensor of RPA-ssDNA after DNA damage and drives ATR activation via a ubiquitin-mediated circuitry. Molecular cell 204 24332808
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2010 mTOR associates with TFIIIC, is found at tRNA and 5S rRNA genes, and targets their repressor Maf1. Proceedings of the National Academy of Sciences of the United States of America 187 20543138
2014 Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes. Molecular cell 173 25544563
2020 UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nature cell biology 168 32807901
2019 H4K20me0 recognition by BRCA1-BARD1 directs homologous recombination to sister chromatids. Nature cell biology 162 30804502
2020 Synthetic Lethal and Resistance Interactions with BET Bromodomain Inhibitors in Triple-Negative Breast Cancer. Molecular cell 159 32416067
2020 A High-Density Human Mitochondrial Proximity Interaction Network. Cell metabolism 148 32877691
2011 Maintenance of silent chromatin through replication requires SWI/SNF-like chromatin remodeler SMARCAD1. Molecular cell 148 21549307
2018 Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains. Molecular cell 136 30554943
2017 RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination. BMC biology 135 29117863
2015 Clinical, histopathologic, and genomic features of Spitz tumors with ALK fusions. The American journal of surgical pathology 130 25602801
2015 FBXW7 modulates cellular stress response and metastatic potential through ​HSF1 post-translational modification. Nature cell biology 130 25720964
2021 Analysis of m6A RNA Methylation-Related Genes in Liver Hepatocellular Carcinoma and Their Correlation with Survival. International journal of molecular sciences 53 33540684
2004 Increased levels of B1 and B2 SINE transcripts in mouse fibroblast cells due to minute virus of mice infection. Virology 33 15351211
2000 Nuclear factor 1 (NF1) affects accurate termination and multiple-round transcription by human RNA polymerase III. The EMBO journal 27 11118217
2022 Genome-wide interrogation of structural variation reveals novel African-specific prostate cancer oncogenic drivers. Genome medicine 26 36045381
2010 Mechanism of down-regulation of RNA polymerase III-transcribed non-coding RNA genes in macrophages by Leishmania. The Journal of biological chemistry 22 21149457
2018 Comparative analysis of single-cell RNA sequencing data from mouse spermatogonial and mesenchymal stem cells to identify differentially expressed genes and transcriptional regulators of germline cells. Journal of cellular physiology 17 29194616
2016 Bioinformatics Analyses of Differentially Expressed Genes Associated with Acute Myocardial Infarction. Cardiovascular therapeutics 15 26725916
2010 Leishmania-induced repression of selected non-coding RNA genes containing B-box element at their promoters in alternatively polarized M2 macrophages. Molecular and cellular biochemistry 14 21165676
2020 The transcription factor Sp1 modulates RNA polymerase III gene transcription by controlling BRF1 and GTF3C2 expression in human cells. The Journal of biological chemistry 13 32115405
2022 Transcription factor GATA4 drives RNA polymerase III-directed transcription and transformed cell proliferation through a filamin A/GATA4/SP1 pathway. The Journal of biological chemistry 11 35038452
2024 Disruption of pulmonary microvascular endothelial barrier by dysregulated claudin-8 and claudin-4: uncovered mechanisms in porcine reproductive and respiratory syndrome virus infection. Cellular and molecular life sciences : CMLS 10 38806818
2006 A test of the model that RNA polymerase III transcription is regulated by selective induction of the 110 kDa subunit of TFIIIC. Nucleic acids research 10 16822860
2022 A comprehensive study based on exosome-related immunosuppression genes and tumor microenvironment in hepatocellular carcinoma. BMC cancer 9 36550445
2024 Spitz melanocytic neoplasms with MLPH::ALK fusions: Report of two cases with previously unreported features and literature review. Journal of cutaneous pathology 8 38444194
2024 Spitz Melanoma With SLC20A1::ALK Fusion: A Novel Fusion Previously Undescribed in Spitz Melanocytic Neoplasm. The American Journal of dermatopathology 6 38941542
2023 Transcription factor AP-2α activates RNA polymerase III-directed transcription and tumor cell proliferation by controlling expression of c-MYC and p53. The Journal of biological chemistry 5 36707053
2025 GTF3C2 Promotes the Proliferation of Hepatocellular Carcinoma Cells through the USP21/MEK2/ERK1/2 Pathway. Journal of clinical and translational hepatology 1 40385937
2026 Integrative gene target mapping, RNA sequencing, in silico molecular docking, ADMET profiling and molecular dynamics simulation study of marine derived molecules for type 1 diabetes mellitus. Molecular diversity 0 41533020
2025 Differentially Expressed Genes Identify FIGO Stage II Cervical Cancer Patients with a Higher Risk of Relapse in a Small Cohort. Journal of personalized medicine 0 41149858